Rasmussen, J; Mahler, J; Beschorner, N; Kaeser, SA; Häsler, LM; Baumann, F; Nyström, S; ... Jucker, M; + view all Rasmussen, J; Mahler, J; Beschorner, N; Kaeser, SA; Häsler, LM; Baumann, F; Nyström, S; Portelius, E; Blennow, K; Lashley, T; Fox, NC; Sepulveda-Falla, D; Glatzel, M; Oblak, AL; Ghetti, B; Nilsson, KPR; Hammarström, P; Staufenbiel, M; Walker, LC; Jucker, M; - view fewer (2017) Amyloid polymorphisms constitute distinct clouds of conformational variants in different etiological subtypes of Alzheimer's disease. Proceedings of the National Academy of Sciences , 114 (49) pp. 13018-13023. 10.1073/pnas.1713215114.

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Abstract

The molecular architecture of amyloids formed in vivo can be interrogated using luminescent conjugated oligothiophenes (LCOs), a unique class of amyloid dyes. When bound to amyloid, LCOs yield fluorescence emission spectra that reflect the 3D structure of the protein aggregates. Given that synthetic amyloid-β peptide (Aβ) has been shown to adopt distinct structural conformations with different biological activities, we asked whether Aβ can assume structurally and functionally distinct conformations within the brain. To this end, we analyzed the LCO-stained cores of β-amyloid plaques in postmortem tissue sections from frontal, temporal, and occipital neocortices in 40 cases of familial Alzheimer's disease (AD) or sporadic (idiopathic) AD (sAD). The spectral attributes of LCO-bound plaques varied markedly in the brain, but the mean spectral properties of the amyloid cores were generally similar in all three cortical regions of individual patients. Remarkably, the LCO amyloid spectra differed significantly among some of the familial and sAD subtypes, and between typical patients with sAD and those with posterior cortical atrophy AD. Neither the amount of Aβ nor its protease resistance correlated with LCO spectral properties. LCO spectral amyloid phenotypes could be partially conveyed to Aβ plaques induced by experimental transmission in a mouse model. These findings indicate that polymorphic Aβ-amyloid deposits within the brain cluster as clouds of conformational variants in different AD cases. Heterogeneity in the molecular architecture of pathogenic Aβ among individuals and in etiologically distinct subtypes of AD justifies further studies to assess putative links between Aβ conformation and clinical phenotype.

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